Homocoupling of halotropones promoted by bis(1,5-cyclooctadiene) nickel in the presence of tris(1-pyrazolyl)methane: an easy route to [Bi-1,3,5- cycloheptatrien-1-yl]-7,7'-diones

Article abstract of DOI:10.1080/00397910802563404

An efficient homocoupling of 2-halotropones, to afford 2,2'-bitropones, occurs in toluene at rt in the presence of stoichiometric amounts of [Ni(cod)2] and tris(1-pyrazolyl)methane ligand, in a 1:1 molar ratio. This methodology was extended to aryl halides. Copyright Taylor & Francis Group, LLC.

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Homocoupling of Halotropones
Promoted by Bis(1,5-
cyclooctadiene) Nickel in
the Presence of Tris(1-
pyrazolyl)methane: An
Easy Route to [Bi-1,3,5-
cycloheptatrien-1-yl]-7,7′-
diones
Tiziana Funaioli a & Marino Cavazza a
a Department of Chemistry and Industrial Chemistry,
University of Pisa , Pisa, Italy
Published online: 02 Apr 2009.
To cite this article: Tiziana Funaioli & Marino Cavazza (2009) Homocoupling of
Halotropones Promoted by Bis(1,5-cyclooctadiene) Nickel in the Presence of Tris(1-
pyrazolyl)methane: An Easy Route to [Bi-1,3,5-cycloheptatrien-1-yl]-7,7′-diones,
Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 39:9, 1592-1600, DOI: 10.1080/00397910802563404
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Synthetic Communications1, 39: 1592–1600, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802563404
Homocoupling of Halotropones Promoted by
Bis(1,5-cyclooctadiene) Nickel in the Presence
of Tris(1-pyrazolyl)methane: An Easy Route
to [Bi-1,3,5-cycloheptatrien-1-yl]-7,70-diones
Tiziana Funaioli and Marino Cavazza
Department of Chemistry and Industrial Chemistry, University of Pisa,
Pisa, Italy
Abstract: An efficient homocoupling of 2-halotropones, to afford 2,20-bitro-
pones, occurs in toluene at rt in the presence of stoichiometric amounts of
[Ni(cod)2] and tris(1-pyrazolyl)methane ligand, in a 1:1 molar ratio. This
methodology was extended to aryl halides.
Keywords: Halotropones, homocoupling, nickel, tris(pyrazolyl)methane
INTRODUCTION
Direct coupling of aryl halides under catalysis by zero-valent nickel
reagents is known to provide an effective entry to symmetric biaryls
under mild conditions with high yield. The original Semmelhack’s
conditions,[1] which require stoichiometric amounts of expensive and
air-sensitive bis(1,5-cyclooctadiene) nickel ([Ni(cod)2]) in dimethylform-
amide (DMF), were repeatedly modified and improved in the ensuing
37 years.[2] Importantly, the active nickel(0) complex was prepared in situ
from air-stable complexes,[3–7] or salts,[8–12] both in stoichiometric[3,5] and
catalytic amounts,[4,6,7,10–12] via chemical (Zn[3–7,9,10] or other metals[8,10–12]
)
or electrochemical reduction[13,14] in the presence of triphenylposphine
and=or an appropriate ligand.[10,15,16]
Received August 7, 2008.
Address correspondence to Tiziana Funaioli, Dipartimento di Chimica e
`
Chimica Industriale, Universita di Pisa, Via Risorgimento 35, 56126 Pisa, Italy.
E-mail: tiziana@dcci.unipi.it
1592

Homocoupling of Halotropones
1593
Homocoupling of a few types of aryl halides was thus notably
improved, but limitations remain for other classes of organic halides.
For example, with 2-, 3-, and 4-halotropones, which are prone to give
organometallic compounds in the presence of reducing metals, all modi-
fications to Semmelhack’s recipe give extremely poor yields. This is
because the organotropone that is formed undergoes further reaction
with unreacted halotropone, leading to a complex mixture of products.
It is well known, for example, that Grignard reagents with 2-chlorotro-
pone mostly give ring-contraction products or products of C-7 addi-
tion.[17] Thus 2-, 3-, and 4-chloro- and bromotropone at 50ꢀC for 3 h in
the presence of a catalytic amount of Ni(0) formed in situ by reduction
of [NiBr2(PPh3)2] with active Zn in the presence of Et4NI in benzene gave
2,20-, 3,30-, and 4,40-bitropones, respectively, in poor yields, while the bulk
of the reagents remained unreacted.[6] Prolonged reaction times caused a
further decrease in the yields.[6] With samarium,[12] which is reported to
tolerate a variety of functional groups and give high yields under mild
conditions, 2-chlorotropone led to only traces of homocoupling product
in our hands (see Experimental, method C).
This article deals with the stoichiometric homocoupling of 2-halo-
tropones and aryl halide promoted by [Ni(cod)2] in the presence of the
tris(1-pyrazolyl)methane (TPM) ligand.
RESULTS AND DISCUSSION
Because the presence of the reducing metal for the active Ni(0) species
in situ production is detrimental for homocoupling of halotropones, we
turned to the original Semmelhack conditions.[1] Starting with 2-chloro-
tropone (1), 2-bromotropone (2), and 2-chloro-4-isopropyltropone (3),
moderate yields of homocoupled products were obtained, along with
appreciable amounts of reduction products (Table 1 and Experimental).
Table 1. [Ni(cod)2]-catalyzed homocoupling of halotropones in DMF (Semmel-
hack’s conditions)
Reaction Temperature
(ꢀC)
Product and
Product and
Substrate time (h)
coupling yield (%)a reduction yield (%)a
1
2
3
2
2
2
20
20
20
4, 57
4, 69
5, 50
6, 23
6, 24
7, 12
aFrom HPLC analysis.

1594
T. Funaioli and M. Cavazza
Scheme 1. [Ni(cod)2]/TPM-catalyzed homocoupling of halotropones and aryl
halides in toluene.
To minimize reductive processes, improve the yields of homocoupled
products, and simplify the recovery, we devised a new method. As shown
in Scheme 1, halotropones 1 and 2 gave [bi-1,3,5-cycloheptatrien-1-yl]-
7,70-dione (2,20-bitropone) (4) and tropone (6), wereas 3 led to [bi-3-iso-
propyl-1,3,5-cycloheptatrien-1-yl]-7,70-dione (5) and 4-isopropyltropone
(7).[18] The methodology involved adding the halotropone to a stirred
slurry in toluene of a neutral tridentate ligand binding transition metal
such as TPM[19] and [Ni(cod)2] in molar ratio 1.54:1:1 at rt under argon.
Monitoring by high-performance liquid chromatography (HPLC)
gave a clue as to the reaction course. Evaporation of the mixture at
reduced pressure furnished a residue that was subjected to silica-gel
thin-layer chromatography (TLC) to give cleanly the coupling product.
Reaction times and yields of both homocoupling products and reduction
products are given in Table 2.
On increasing the TPM=[Ni(cod)2] molar ratio from 1 to 1.5, the
yields of both 4 and 5 dropped by half.
Attempts to make the Ni(cod)2=TPM homocoupling of 2 using
samarium as reducing metal catalytic resulted in the disappearance
of the starting material, and only traces of both 4 and 6 were found
(see Experimental, method B).
Our methodology was also applied to typical, and frequently investi-
gated, aryl halides, such as p-bromoacetophenone (8), p-bromoanisole
(9), and p-bromoaniline (10) (Scheme 1). With 8, which is activated by
electron-withdrawing MeCO in the p-position, the homocoupling ran

Homocoupling of Halotropones
1595
Table 2. [Ni(cod)2]=TPM-catalyzed homocoupling of halotropones and aryl
halides in toluene
Reaction Temperature
(ꢀC)
Product and Product and
coupling yield (%) reduction yield (%)
Substrate
time (h)
1
2.5
1.5
2.0
6.0
8.0
2.0
20
20
20
20
20
50
4, 77a
4, 81a
6, 8a
6, 5a
2
3
5, 75a
7, 5a
8
11, 80a
12, 74b
13, 56b
14, 0a
15, 26b
16, 44b
9
10
aIsolated yield.
bFrom HPLC analysis.
smoothly, giving biaryl 11 in practically quantitative yield in 6 h at rt
(Table 2). This represents a marked improvement on Semmelhack’s
methodology,[1] where temperatures are higher (45ꢀC) and reaction times
longer (36 h). With substrates carrying electron-donating substituents in
the p-position, such as 9 and 10, we obtained contradictory results. The
bromocompound 9, under our reaction conditions, behaved like those
previously observed,[1,10] whereas 10 reacted slowly and mainly along
the competitive reduction route to give aniline.[20]
The mechanism of these coupling reactions is under investigation.
We reckon that TPM works as an auxiliary ligand, but its behavior seems
1
to differ from 2,20-bipyridine and its derivatives.[16] In fact, H NMR
spectra ruled out any ligand exchange reactions of [Ni(cod)2] with
TPM. Interaction of the TPM ligand probably occurs with a Ni(II) inter-
mediate species arising from the initial process of oxidative addition[10] of
the organic halide to Ni(0). Whatever is its exact role in the reaction
mechanism, TPM makes it possible to use a scarcely polar solvent such
as toluene. We recall that the only solvent that has been found to be
satisfactory for the original Semmelhack coupling reaction is DMF.[1]
Competitive coordination by a reagent such as 10 would lead to low
yields of homocoupling product.
CONCLUSIONS
In spite of some limitations, our methodology provides simple and effi-
cient entries to 2,20-bitropones. It is now feasible to assay the biological
activity of these substrates under fair prospects, given the remarkable
biological activity of the cycloheptatrienone nucleus.[21] If so, the use of
expensive [Ni(cod)2] in stoichiometric amounts would be justified.

1596
T. Funaioli and M. Cavazza
EXPERIMENTAL
General Remarks
Toluene (C. Erba) was distilled from Na under an atmosphere of Ar.
DMF (C. Erba) was distilled from CaO and stored over 30-mm molecular
sieves under an atmosphere of Ar. [Ni(cod)2] (Aldrich) was used as such.
TPM was prepared according to literature.[19] Halotropones[22] 1 and 2
and 2-chloro-4-isopropyltropone[23] (3) were prepared as previously
1
reported. H NMR and 13C NMR spectra were recorded on a Varian
200-MHz spectrometer. All chemical shifts were reported in d units with
reference to TMS (1H) or the signals of the solvent (13C). UV-visible
spectra were recorded on Hitachi 200 Perkin-Elmer spectrophotometer.
HPLC analyses were performed with a Jasco Bip-1 pump equipped with
a Jasco Uvidec-100-V spectrophotometer.
Homocoupling of Halotropones and Aryl Halides in Toluene Promoted by
Bis(1,5-cyclooctadiene) Nickel in the Presence of TPM
[Bi-3-isopropyl-1,3,5-cycloheptatrien-1-yl]-7,70-dione (5)
TPM (0.047 g, 0.219 mmol) was added under Ar to a stirred solution
of [Ni(cod)2] (0.060 g, 0.218mmol) in toluene (6.5 mL). Compound 3
(0.061g, 0.337mmol) was added to the slurry, and the resulting mixture
was stirred at rt for 2 h. Evaporation at reduced pressure of the reaction
mixture led to a residue that was subjected to silica-gel TLC (Et2O,
Rf ¼ 0.33 ) to give [bi-3-isopropyl-1,3,5-cycloheptatrien-1-yl]-7,70-dione (5)
0.037g (0.126mmol, 75% yield) as a colorless solid (mp 145ꢀC) and 4-iso-
propyltropone (7) (nezukone)[18] (Rf ¼ 0.5) (0.0025 g, 0.017 mmol, 5% yield).
Data for 5: Mp 145ꢀC (dec); UV (EtOH) kmax (log E) 310 (4), 237 (4.3)
1
nm; H NMR [200 MHz, (CD3)2CO], d 1.28 (d, J ¼ 7.0 Hz, 6H), 2.90
(heptet, J ¼ 7.0 Hz, 1H), 6.84 (dd, J ¼ 12.2 Hz, J ¼ 1.2 Hz, 1H), 6.96
(ddd, J ¼ 7.60 Hz, J ¼ 1.8 Hz, J ¼ 1.2 Hz, 1H), 7.19 (dd, J ¼ 12.2 Hz,
J ¼ 7.60 Hz, 1H), 7.35 (d, J ¼ 1.2 Hz, 1H); 13C NMR (50.3 MHz, CDCl3)
d 23.4, 38.5, 129.7, 136.2, 137.7, 139.6, 154.9, 185.2. HRMS: found Mþ
294.16186 (0.00012): C20H22O2 requires 294.16198.
[Bi-1,3,5-cycloheptatrien-1-yl]-7,70-dione (4)
Compound 4 was prepared as described for the previous compound
starting from 1 (0.042 g, 0.300 mmol) TPM (0.042 g, 0.195 mmol), and
[Ni(cod)2] (0.053 g, 0.194 mmol). We obtained 0.024 g of bitropone 4

Homocoupling of Halotropones
1597
(0.115 mmol, 77% yield) and 0.0025 g of tropone 6 (0.024 mmol, 8%
yield). When starting from 2 (0.055 g, 0.300 mmol), TPM (0.042 g,
0.195 mmol), and [Ni(cod)2] (0.053 g, 0.194 mmol), we recovered
0.0255 g of bitropone 4 (0.121 mmol, 81% yield) and 0.0016 g of tropone
6 (0.015 mmol, 5% yield). Analytical data agreed with the literature.[6]
4,40-Diacetylbiphenyl (11)
Compound 11 was prepared as described for the troponoids starting
from p-bromoacetophenone (8) (0.069 g, 0.35 mmol), TPM (0.053 g,
0.25 mmol), and [Ni(cod)2] (0.064 g, 0.24 mmol) in 5 ml of toluene. After
6 h at rt, evaporation at reduced pressure of the reaction mixture led to
a residue that was subjected to silica-gel TLC (hexane=AcOEt 80:20,
Rf ¼ 0.27 ) to give 11 (0.033 g, 0.14 mmol, 80% yield). Data for 11 agreed
with those of a commercial (Aldrich) sample.
4,40-Dimethoxy-1,10-biphenyl (12)
Compound 12 was prepared as described for 11 starting from p-bromo-
anisole (9) (0.0445 g, 0.24 mmol), TPM (0.036 g, 0.17 mmol), and
[Ni(cod)2] (0.046 g, 0.17 mmol) in 3.5 ml toluene. After 8 h at rt HPLC
analysis [250-mm column Si 60, eluent n-hexane=(CH3)2CHOH 0.2%,
using standard solution of 12 and 15 (commercial Aldrich products)] gave
76 and 26% yields for 12 and 15 respectively.
Benzidine (13)
Compound 13 was prepared starting from 4-bromoaniline (10) (0.035 g,
0.20 mmol), TPM (0.031 g, 0.145 mmol), and [Ni(cod)2] (0.039 g,
0.142 mmol). After stirring for 2 h at 50ꢀC, HPLC analysis [250 mm
column Lichrosorb CN, eluent n-hexane=EtOAc 50:50 using standard
solutions of commercial available (Aldrich) 13 and 16] gave 56 and
44% yields for 13 and 16 respectively.
Homocoupling of Halotropones and Aryl Halides Promoted by
Bis(1,5-cyclooctadiene) Nickel in DMF (Semmelhack’s Methodology)[1]
Bi-1,3,5-cycloheptatrien-1-yl]-7,70-dione (4) and [Bi-3-isopropyl-1,3,5-
cycloheptatrien-1-yl]-7,70-dione (5)
DMF solutions of halotropones 1, 2, and 3 0.05 M and [Ni(cod)2] 0.03 M
were prepared and stirred under Ar for 2 h at rt The yields of the

1598
T. Funaioli and M. Cavazza
reactions were determined by HPLC analysis (250-mm column
Lichrosorb CN, eluent EtOAc) using standard solutions of 4, 5, 6, and 7.
From 1 and 2, we obtained 4 in 57 and 69% yields and 6 in 23
and 24% yields, respectively, whereas 3 gave 5 in 50% yield and 7 in
12% yield.
Homocoupling of Halotropones Promoted by Ni(0) in Catalytic Amounts
Method A
Compound 1 (0.085 g, 0.605 mmol) was dissolved under Ar in DMF
(8.5 mL) containing Zn (0.075 g, 1.15 mmol), (C6H5)3P (0.080 g,
0.305 mmol), and [Ni(cod)2] (0.0085 g, 0.030 mmol). The mixture was
stirred at rt, and the reaction was monitored with HPLC (250-mm
column Lichrosorb CN, eluent EtOAc) using standard solution of 4
and 6. After 4 days, ca. 70% of troponoid disappeared and only traces
of bitropone were detected.
Method B
Compound 1 (0.072 g, 0.513 mmol) was dissolved under Ar in DMF
(7.2 mL) containing Sm (0.129 g, 0.858 mmol), TPM (0.029g, 0.135 mmol),
and [Ni(cod)2] (0.0072 g, 0.026 mmol). The mixture was stirred at rt, and
the reaction was monitored with HPLC as before. After 20h, the reaction
was complete, and only traces of both 4 and 6 were found.
Method C
Compound 1 (0.072 g, 0.513 mmol) was dissolved under Ar in DMF
(7.2 mL) containing Sm (0.137 g, 0.911 mmol), (C6H5)3P (0.076 g,
0.289 mmol), and [Ni(cod)2] (0.0076 g, 0.028 mmol). The mixture was
stirred at rt, and the reaction monitored with HPLC as before. After 20 h,
the reaction was complete, and only traces of both 4 and 6 were found.
ACKNOWLEDGMENT
`
T. F. thanks Ministero dell’Istruzione, dell’Universita e della Ricerca
(MIUR), Programmi di Ricerca Scientifica di Notevole Interesse
Nazionale 2004–2005, for financial support.

Homocoupling of Halotropones
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